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spk14: Good day, ladies and gentlemen, and welcome to Acadia Pharmaceutical's third quarter 2022 financial results conference call. My name is Gigi, and I'll be your coordinator for today. At this time, all participants are in listen-only mode. We will be facilitating a question and answer session towards the end of today's call. I would now like to turn the presentation over to Mark Johnson, Vice President of Investor Relations at Acadia. Please proceed.
spk09: Thank you, Gigi.
spk05: Good afternoon and thank you for joining us on today's call to discuss Acadia's third quarter 2022 financial results. Joining me on the call today from Acadia are Steve Davis, our chief executive officer, who will provide an overview of our third quarter performance and a review of our business. Brendan Ian, our chief operating officer, head of commercial, will provide updates on our commercial performance. And Kathy Bishop, our chief scientific officer and head of rare disease, will provide an overview of terpenetide. Dr. Serge Sankovich, our president, will then discuss our pipeline progress And Mark Schneier, our Chief Financial Officer, will discuss our financial results and guidance before turning it back to Steve for final remarks and opening the call up for your questions. I would also like to point out that we're using supplement slides, which are available on the events and presentation section of our website. Before we proceed, I would first like to remind you that during our call today, we will be making a number of forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements, including goals, expectations, plans, prospects, growth potential, timing of events, or future results are based on current information, assumptions, and expectations that are inherently subject to change and involve a number of risks and uncertainties that may cause actual results to differ materially. These factors and other risks associated with our business can be found in our filings made with the SEC. We're cautioned not to place undue reliance on these forward-looking statements, which are made only as of today's date. I'll now turn the call over to Steve.
spk06: Thank you, Mark. Good afternoon, everyone, and thank you for joining us today. Please turn to slide five. As we present the last quarter, to achieve our mission, we're investing our resources to optimize our commercial investment in Parkinson's disease psychosis, preparing for the launch of TRIPMCAT for Rett syndrome, and positioning ourselves for long-term success through internal R&D and strategic business development. With PDP, we are focused on investing in the highest ROI activities that efficiently drive demand for the brand and maximize the value of the new Pfizer franchise. In addition, investing for a successful launch of terpenetab for the treatment of Rett syndrome, our potential second commercial product. We're investing in our pipeline of late and early stage clinical candidates, most notably our negative symptoms of schizophrenia phase three program and our ACP 204 phase one program. And finally, we continue to position ourselves to leverage an increasingly attractive opportunity set for business development in CNS and rare disease. The positive cash flow from our New Planset franchise allows us to invest in our future growth opportunities without the need to raise additional capital. Let's turn to slide six. For the third quarter, New Planset achieved $130.7 million in net sales. This was driven by a sequential demand growth of 2% and an acceleration of growth in the long-term care channel. Revenues were offset by a reduction of in-channel inventory, impacting net sales by approximately $7 million. I'd like to highlight a couple of items related to the current landscape for new classes. Recently, we've seen an increase in prescription growth in the LTC channel, as this segment is starting to show early signs of improvement. This is driven by an incremental but steady increase in LTC occupancy rates, supported by an increase in new admissions. As Brendan will elaborate, a new admission is a critical time for a potential diagnosis of psychosis and potential treatment with new classes. However, the in-office channel continues to be unchanged and is still impacted by fewer in-person patient visits with their doctors as compared to pre-pandemic levels. Here we have not yet observed the same level of incremental improvements as we have in the LTC channel. As we look forward, we will continue to evaluate and execute on the best ways to optimize and maximize our PDP business, which as a reminder has been cash flow positive since 2019. Let me highlight a couple of important dynamics. One, our relative outperformance since the beginning of the pandemic on total scripts of nucleoside when compared to baskets of the top Parkinson's, neurology, and LTC medicines, together with our ability to increase share in a constrained environment, give us confidence in our ability to maximize the brand in the long run. And two, the recent publications and presentations of real-world studies comparing the use of nucleoside to other antipsychotics highlight and expand on the favorable safety profile of nucleoside for use in PDP patients. We will continue to support the dissemination of these important data sets within the treating community. Let's move on to our late stage programs on slide seven. We're in prelaunch preparations while in parallel facilitating the FDA's review of our new drug application for terpenetide in Rett syndrome. We announced in the quarter that the FDA granted priority review for our MDA file and assigned a PDUFA action date of March 12, 2023. For approved, we'll be the first and only FDA-approved treatment for Rett syndrome. In addition, we would expect to receive a pediatric priority review voucher. Our commercial team is working diligently on preparing for launch, including market development, disease state education, consumer profiling, and broader care team identification. Next, we expect to complete enrollment in our Negative Symptoms of Schizophrenia Phase 3 study, Advance 2, around the middle of next year. Today, we estimate that there are over 700,000 schizophrenia patients receiving treatment with antipsychotic therapy in the U.S. who still have persistent and impactful negative symptoms. And as we've previously described, there is no FDA-approved drug for the treatment of these negative symptoms. For context, this is about five times the size of the PDP market where Neuplizer is currently approved. If approved, an advancement would be indicated as an adjunct therapy that would not need to replace or compete against first-line generic drugs. Let's now turn to slide eight to discuss our early-stage programs. As we mentioned last quarter, we've been working on a new molecule, ACP204, for the past few years and are currently in phase one development. Acadia developed ACP204 internally and maintains worldwide rights with no economic obligation to any third party. ACP204 is designed to leverage the learnings from Pima-Vanturin, and hits a nice sweet spot. It shares some important similarities to Pima-Vanturin, which provide the potential for reduced development risk, and also is designed to explore important opportunities for improvement. In addition, we remain excited about our other early stage programs, including our collaboration with Stoke Therapeutics. And we will continue to develop and invest in our pipeline while evaluating and investing in business development. leveraging our internal commercial and R&D expertise across psychiatry and neurology in broad and rare disease areas. To discuss our commercial efforts in greater detail, I'll now turn it over to Brandon.
spk07: Thank you, Steve. Please turn to slide 10. Our commercial team continues to perform at a high level and deliver demand growth for New Placid quarter over quarter. As Steve mentioned, for the third quarter of 2022, Complazas achieved $130.7 million in net sales. This was driven by sequential demand growth of 2% with particular demand acceleration demonstrated in the long-term care channel. Let's start with LTC. As shown in the graph on slide 10, we have delivered sustained growth since the bottom of the pandemic, which was the first quarter of 2021. Recall the LTC channel experienced significant declines early in the pandemic. And while things have been improving modestly, you will note that the occupancy rates remain significantly suppressed today from where they were pre-pandemic. The recent improvement in occupancy rates over this period is one contributor to New Placid's growth in LTC. More specifically, the growth occurs in an environment of increased new resident admissions. This is important as new admissions are a critical time for the diagnosis of the symptoms of psychosis and the selection of New Placid. This rise in new admissions, coupled with our proprietary data sources that help our teams focus on facilities with the highest number of PD residents, enable us to target the best opportunities to treat newly diagnosed PDP patients in this key market segment. As you can see, in this environment of modest LTC occupancy growth, New Plaza's growth rate has outperformed these improvements. In fact, we are delivering some of the strongest prescription growth we've ever had in this segment. Looking at the office space channel, while our market share has grown over the pandemic, albeit at a slower rate, we're still constrained by a lack of meaningful improvements in in-office patient visits with their physicians. This is a critical time for the diagnosis of the symptoms of psychosis and a prescription for a new plazit. Looking ahead, our team is now sharing data from real-world studies with physicians and payers. These studies evaluated the safety of treatment with Nuplazid in the PDP population versus off-label antipsychotics. For example, starting in the middle of the third quarter, in the LTC channel, we started to share with payers some of the recently presented retrospective study of a PDP Medicare claims database, which concluded that Pima-Vansarin treatment resulted in lower all-cause and psych-related hospitalizations, lower all-cause and psych-related emergency room visits, and fewer nursing facility stays versus off-label atypical antipsychotics. In addition to fewer stays, patients on Pima-Vansarin had shorter stays in hospitals and facilities. More recently, starting in the early fourth quarter, we've been sharing a recent publication with physicians that highlights the safety profile of Nuclasid compared to treatment with off-label antipsychotics and PDP. These are important data for clinicians to understand when making treatment decisions for patients and residents facing PD psychosis symptoms in the first-line setting. We will continue to thoughtfully invest, mindful of the gradual normalization of the PDP market, optimizing our PDP investments on the highest ROI activities. We're focused on both top-line and bottom-line growth for the New Plaza franchise. which enables us to invest in our newest growth opportunity, Trofinitide, as well as the R&D portfolio. Let's now turn to our prelaunch strategy and activities for Trofinitide on slide 11. As we look ahead to the launch of Trofinitide, we see a tremendous opportunity to improve the lives of patients and caregivers suffering from Rett syndrome. Trofinitide is a significant growth opportunity for us, and we're investing appropriately to deliver a successful launch. Today, our efforts are focused on pre-launch market development as well as the build-out of our commercial and medical organizations. Important to every launch, but especially in a rare disease like Rett syndrome with no approved treatment, is the focus on disease education and awareness of the unmet need of those living with or caring for someone with Rett. For years, Rett treaters have had very limited options, only being able to treat some of the non-core symptoms of Rett syndrome, such as seizure burden or constipation. At the same time, caregivers live with a daily uncertainty of RET and are often not able to get help with core symptoms that have a profound impact on daily life. Symptoms such as hand-wringing, purposeful eye gaze, and communication, which to date cannot be fully addressed, in part because there are no treatments available to address these needs. The opportunity exists to establish a shared understanding of RET and to foster less fragmented, seamless communication across the care team and caregivers and ultimately turn the spotlight on the still unmet, untreated core symptoms of the disease that matter to caregivers and that profanity may address. That is where we're focused today. As an illustration of these efforts, at the recent Child Neurology Society Conference, which included many of our target pediatric neurologist providers who treat Rett, we launched rettdialogue.com. a website focused on shedding the light on the current limitations in care and increasing physician awareness of the breadth and depth of needs to address the core symptoms of Rett syndrome. To supplement these educational efforts, our medical team is presenting our clinical data at important medical and market access congresses, highlighting the potential clinical value proposition of terpenetide with KOLs and payers. We are additionally preparing for launch by augmenting our customer-facing team with our rare disease commercial organization. We have made substantial progress in building our seasoned leadership team with breadth and depth of rare disease expertise while leveraging the existing elements of our neurology franchise. Today we know there are approximately 4,500 RET patients diagnosed and treated in the United States and are cared for at IRSF-designated centers of excellence, non-COE academic institutions, and other targeted neurology practices. We are already mapping our HCP target universe and patient database, so our field force will know where best to target our treating audience at launch and beyond. In addition to our targeting work, we recognize how critical it is to provide caregivers and physicians with end-to-end support they need to help patients start and stay on therapy and ensure an optimal treatment experience. This is a key area of investment for our team. Finally, I'd like to mention that October was Rett Syndrome Awareness Month, and we were proud to support disease awareness and educational activities across the United States within the Rett community. Our ultimate launch objective will be to establish tropinotide as the foundational treatment for Rett Syndrome and ensure access to all patients in need, and we're well on our way to achieving that goal. I'll now turn it over to Kathy to continue our discussion on tropinotide.
spk19: Thank you, Brendan. Please turn to slide 13. As you know, Rett syndrome is a serious and debilitating rare disorder for which there is no FDA-approved treatment. We estimate there are between 6,000 and 9,000 patients in the United States with Rett syndrome, and we have data indicating there are approximately 4,500 patients currently diagnosed and being treated. As Brendan briefly mentioned, we continue to present clinical data for trypanotide at important medical congresses for the REC community, including at the recent American Academy of Pediatrics and Child Neurology Society meetings. This includes the positive phase 3 lavender study results, where we hit both co-primary endpoints and our key secondary endpoints. We also presented interim data from our DASA DIL study in younger Rett syndrome girls aged 2 to 4. As you may recall from the Phase III lavender study, we observed consistent results across age groups and severity of disease. These additional data have been submitted to the FDA in support of our NDA for triphenotype. In addition, we are pleased with the positive feedback and enthusiasm we are receiving from both the medical community and the caregivers at these events as we approach a potential Trifinitide approval. During the quarter, the FDA accepted our application for filing and granted us priority review. Our PDSA action date is March 12th of 2023. And the FDA continues to indicate that they're not planning to hold an advisory committee meeting. And I'll now turn it over to Serge for an update on our other pipeline programs.
spk10: Thank you, Cathy. Good afternoon, everyone. Let's move on to our second potential indication for PIMA Lancery, starting on slide 15. Persistent negative symptoms of schizophrenia remain one of the largest unmet needs in CNS. And as of today, there are still no approved treatments for these symptoms, which can lead to low social functioning, long-term disability, and significant caregiver burden. We are evaluating pimavanserin for those patients whose positive symptoms are controlled on currently available antipsychotics, but continue to experience predominant negative symptoms. We believe pimavanserin can be effective as an adjunctive treatment to help close that gap. As part of our development program, we have one positive pivotal study, ADVANCE-1, where we observed statistical separation on the primary endpoint overall, and even more robust results in patients receiving 34 milligrams of pimavanserin compared to the lower doses. To maximize the probability of success in our ongoing phase three study, advanced two, we have optimized the dosing using only the 34 milligram dose of pimavanserin compared to placebo. We remain on track for enrollment completion around the middle of next year. As a reminder, this is a six-month study duration. We look forward to keeping you updated on our progress. Now let's discuss our ACP204 program on slide 16. ACP204 is a new molecule which is designed to leverage the learnings from PrimaVanserin. For several years, we have sought to build upon our PrimaVanserin franchise by investigating and developing other molecules focused on the serotonergic system. Remember, virtually all of the antipsychotics on the market today are thought to work predominantly through blocking dopamine, and in particular, the dopamine D2 receptor. Pimavene vancerin is thought to work entirely through serotonin, which can provide a very different and favorable safety and tolerability profile. Of course, small molecules, especially in early clinical development, have high attrition rates. But with HCP204, we are working with a known mechanism, and we have a good understanding of where to go and where not to go in the chemical space, so our risk profile is mitigated to some extent. Specifically, with HCP204, we may have an opportunity to maximize the efficacy potential while reducing the risk of QT prolongation. We are currently in phase one development. We have advanced phase one studies covering our targeted dose range based on the preclinical in vitro and in vivo data. Clinical data today support the targeted dose range and also may allow exploration of additional higher exposure. We plan to complete this additional phase one work in order to finalize doses to be evaluated in phase two and three studies. In respect to potential indications to evaluate, there are a lot of opportunities with Alzheimer's disease psychosis being at the top of that list. With that, I will turn the call over to Mark to discuss our financials.
spk08: Thank you, Serge. Let's start by reviewing our quarterly financial performance on slide 18. In the third quarter, we recorded $130.7 million in net sales, driven by 2% sequential demand growth in the second quarter. While our inventory levels continue to be within historical averages, we did experience a reduction of in-channel inventory during the quarter, which impacted net sales by approximately $7 million. Our gross to net adjustment increased to 18.6% during the quarter compared to 15.2% in the third quarter of last year. The increase in gross to net is primarily due to these two factors. One, an increase in 340B volumes, and two, a higher gross to net adjustment to account for in-channel inventory rebates associated with the Inflation Reduction Act, which I will speak to more in a moment. GAAP R&D expenses increased to $81.3 million in the quarter compared to $58.6 million in Q3 2021. The increase was primarily due to a $10 million milestone payment accrued to NURIN upon the acceptance of the tropenotide NDA filing and increased cost of our commercial supply for tropenotide of approximately $8 million, the cost of which are classified as R&D expenses prior to approval. GAAP SG&A expenses decreased to $78.1 million in the third quarter from $81.7 million in the third quarter of last year. On a year-to-date comparison to 2021, net sales were up 8% and SG&A expenses were down 9% as we continue to optimize our commercial PDP spend. R&D expenses were higher than 2021, primarily due to the $60 million upfront for the Stoke collaboration $10 million Neuron Milestone, and approximately $18 million of Trepidatide Commercial Supply Bill. And finally, we ended the quarter with a cash balance of $436.6 million, essentially unchanged from the $436.4 million cash balance at the end of the last quarter. Our balance sheet remained strong, and we continue to be confident in our ability to generate sustainable growth with our existing cash resources, subject to the size and scope of future business development. Before I give an update on guidance, let's address the newly passed Inflation Reduction Act on slide 19. As a reminder, the IRA is focused on Medicare beneficiaries and New Plaza has a payer mix that includes approximately 75% Medicare patients, whereas we expect your kinetized payer mix to have a Medicare population less than 10%. We have assessed various aspects of the legislation including potential implications of the inflation-adjusted pricing mechanism as well as the Medicare Part D redesign, inclusive of the small manufacturer phasing. All in all, while there are several puts and takes from either year, we expect the overall financial impact on Acadia to be relatively modest for the remainder of the decade. The Inflation Reduction Act did have an impact on our most recent pricing action from August 2022. Earlier in the summer, we initiated the process to implement the 9.4% price increase on New Placid, which we completed in late August. As a result of the IRA, which went into effect during this time, we will realize a net pricing benefit of approximately 3% from this latest pricing action. The 3% net price benefit will last through the end of the third quarter of 2023, after which it will be reassessed against an updated inflation-adjusted price as of October 1, 2023. The approximate 6% difference between the nominal and net price change from our August pricing action will result in an additional Medicare rebate, which will be accounted for as an increase to our gross to net adjustment. Let's move on to our financial guidance on slide 20. Regarding next sales guidance for this year, we are now guiding for a range of $510 to $520 million. The midpoint of the range assumes that we continue to have similar demand for new plaids for the remainder of 2022. In addition, it reflects the inventory drawdown we experienced this quarter and the 2022 impact of the Inflation Reduction Act. We have increased our growth to net guidance to a range of 21% to 22% for fiscal year 2022 to account for additional Medicare rebates associated with the Inflation Reduction Act. In addition, we are tightening our expense ranges for the midpoint to remain unchanged. We are also tightening our expected year-end cash balance raising the bottom of the range by $15 million. And now I'd like to turn the call over to Steve for closing remarks.
spk09: Great. Thank you much, Mark. Please turn to slide 22.
spk06: Today we are executing on our promise to deliver new plans to patients with PDP with a focus on long-term growth and maximizing the value of the franchise. In addition, we are preparing for our second commercial product launch with Tripinidat. We're advancing our phase three program for the negative symptoms of schizophrenia and developing several additional programs, including ACP204, while pursuing attractive business development opportunities. With a strong balance sheet and a focus on top and bottom line growth, we are well positioned to create sustainable long-term value. As always, I would like to thank our employees for their accomplishments and their ongoing commitment and passion as we continue our mission to elevate life. Before moving to Q&A, I'd like to mention that Acadia has recently appointed Dr. Adora Indu to its board of directors. Adora is a biopharma executive with significant regulatory and clinical experience. Combined with her extensive background in rare disease, her skill set nicely complements those of our current board membership and will be a real asset to us as we further commercialize and expand our pipeline. And finally, as you may have seen in our announcement last week, Surge, our president, will be retiring at the end of the year. Over the past seven years, Surge has been a great partner as we fundamentally transformed Acadia into what it is today, a commercial stage biopharmaceutical company with proven capabilities and exciting portfolio of late and early stage programs in CNS and rare disease. Personally, it's been a great pleasure to work alongside Surge, and I hope you will join me in thanking him for his distinguished service to Acadia the scientific community, and most importantly, to patients and their families. Going forward, Serge will transition to an advisory role and will continue to benefit from his keen insights and vast experience. I'll now open up the call for questions. Operator?
spk14: Ladies and gentlemen, if you wish to ask a question, please press star followed by 1-1 on your touchtone telephone. please limit yourself to one question. I repeat, please limit yourself to one question. Press star 11 to begin. Please stand by for your first question. Our first question comes from the line of Charles Duncan from Cantor Fitzgerald.
spk18: Hi. Yeah. Hi, Steve and team. Thanks for taking the question and appreciate all the detail, um, particularly on, on, uh, team of answering our new Placid. Um, but I'll, I'll limit my one question to a multi-part question on, on RET and Trophinatide. I guess I'm wondering with the PDUFA date, do you anticipate that manufacturing inspections are yet to be done or have they been done? And then secondarily, I think Kathy mentioned additional data from Daffodil was submitted. Was that submitted before or was it submitted with the package or was it submitted after the package? And then finally, with regard to the PRV, and you may not be able to answer this right now, but would you anticipate using that internally or monetizing that? Thank you.
spk06: Thanks much. Charles, let me take the first one and the third one, and then I'll ask Kathy to respond to the middle question. Actually, just starting with the third, it's just premature for us to say what we would do with the pediatric review voucher. I think in terms of your question regarding the manufacturing inspections, as we've said previously, our policy is just not to comment on day-to-day interactions or back and forth during a review period. What I will say, though, is from all indicators that we have, the review appears to be exactly on track and we're eager to get to the PDUCA data.
spk19: And Charles, I'll just clarify for your second question regarding the interim data from the long-term extension studies as well as from the DASA study in the younger girls aged two to four, that interim data was submitted as part of the NDA, the original NDA filing.
spk17: Okay, very good. That's helpful. I'll hop back in the queue. Thank you.
spk14: Thank you. One moment for our next question. Our next question comes from the line of Nina Vitrudo-Gard from Citi.
spk13: Hey, guys. Thanks for taking my question. I just want to ask about New Plaza and if you can comment on The proportion of sales now coming from the long-term care channel, I know you've said historically it's been about 25% if that's changed at all. And then what you think it will take to get patients coming back into the in-office channel and why you think admission rates are going up in LTC but in-office visits are still lagging. Thanks.
spk06: Sure. Thanks much for the question, Zia. Brendan, you want to address that?
spk07: Sure. Hey, Nina, thanks for the question. I'm encouraged by what we're seeing in the long-term care channel, and I should say that we've had an increase in prescription growth quarter over quarter, and it is an indication of early signs of improvement. We think that's driven by occupancy rates that have gradually increased over the last several quarters, but for us, the most important element of that are the new residents that are showing up. And I think that's a really important contrast to the in-office channel. When a new resident shows up, there's a clinical evaluation that takes place. That's an ideal time for the identification of Parkinson's disease psychosis symptoms and a great chance for a start on Nuplazid. We've seen quarter over quarter that Nuplazid's growth rate is outpacing Carbidopa levodopa. It's also outpacing the top 15 neurobrands. of the top 15 LTC brands in the space, which gives us a sense that both the clinical proposition of New Pleasant and that market dynamic is working to our advantage. The difference in the in-office channel is that there was a decline in the number of patients with in-office visits at the beginning of the pandemic. I think what is encouraging is that we've seen that stabilize. So it's at a lower level, but it hasn't continued to decline. I'm encouraged on two levels there. One, there is an incidence rate for Parkinson's disease, and we would fully expect patients to begin to return more readily to the office. And secondarily, in this marketplace, we are going to continue to compete for first-line use, as I mentioned in my prepared remarks, with the real-world evidence that we have available to us that further differentiates Nuplazid from other off-label atypical antipsychotics. in a way that we don't think clinicians have seen previously. So, you'll see our focus is on share gain and looking for more first-line use of new plazas in that setting. And yes, I'm sorry, I can also confirm that LTC is still roughly about 25% of our overall bottle mix.
spk14: Got it. Thank you. Thank you. One moment for our next question. Our next question comes in the line of Ritu Baral from Cowen.
spk11: Good afternoon, guys. Thanks for taking the question. And Serge, wishing you all the best in your next stage. It's been great working with you for 10 years, almost 10 years now from this side. I guess the question is for you and Steve. And Steve, I know you won't comment on day-to-day interactions with the agency. But just given the next to last review cycle that you guys had with a different division, but with DRP, I guess investors that I'm speaking to just want some level of comfort that this review cycle is going differently than the original DRP where you had pretty much no communications during that period. I guess Can you give us any color or compare and contrast on things like mid-cycle review meetings or any requests for information that may have come and passed and, you know, just something to show us that the track is different from what has happened with neuropsych in the past?
spk06: Yeah, yeah. No, thanks for the question. I think two things I can, I'll give as much color as I can, and two things I can point out. One is this is a NDA. And, of course, with DRP slash ADP, it was an S NDA. And so with an S NDA, you just don't have as much structured milestones. And so it's a little bit looser. And so, you know, an advantage, of course, of going through the NDA process in comparison is you do have more structured milestones. And as I mentioned earlier, it appears from all we can see that the FDA is right on track. The second thing I'll mention is also with an SMDA, because you don't have many structured milestones, sometimes you just don't have as much dialogue and communication during the review cycle. And we didn't have very much with that application. We have had the appropriate level of communication. It's significantly more than we had with the last application, but we've continued to have a very productive and appropriate dialogue throughout the review period.
spk11: Got it. That's very helpful. I'm going to squeak one last question in for Serge. Serge, you mentioned 204. Can you give us some sort of update on timing for when you may formally announce additional indications for 204 and when those phase 2s might start?
spk10: Yes. Thank you, Ritu. First, thank you for your kind words, and I just want to say that it equally was my pleasure to work with you and to work with this broader group. You guys always have very thoughtful and thought-provoking questions, and it's been really a great pleasure to periodically update you on the progress of our program. So that's the part that I will miss, among many things, as I slow down in the future period. In regard to HCP 204, it's a little bit premature for us to talk about about indications. As I said, there is a number of potential indications. Very high on the list is Alzheimer's disease psychosis, as you can imagine. There is a little bit of work for us to complete in the phase one. The good news is that based on the work we already completed, there is an opportunity for us to look to a higher exposure ranges than our target doses that, based on our preclinical data, we assigned and targeted. So that's great news. And in neuropsychiatric indications, as you know, it's always good to define a broader range. We have not yet defined minimum tolerated dose. So it's a great opportunity for us to expand that range, and we would like to take a little bit more time to complete that work. And following that, when we complete that, we will be more open to discuss potential indications and the development plan that we are thinking about.
spk11: Great, thanks.
spk14: Thank you. One moment for our next question. Our next question comes from the line of Tazin Ahmad from Bank of America Merrill Lynch.
spk16: Hey guys, this is Daniel for Tazin. Thank you for taking our question. We've got a quick question on 204. and the opportunity for ADP. I'm just wondering what you were thinking about in terms of the competitive landscape down the line with M1 and M4 agonists also moving into that space. And maybe any comments on how the different mechanisms of action might play into that indication.
spk06: Yeah, thanks much for the question. I think I'd like to draw a distinction between kind of the ideal profile for an antipsychotic drug to treat schizophrenia and an antipsychotic drug to treat a much more frail or elderly population like Parkinson's disease psychosis or Alzheimer's disease psychosis. You know, what we have with drugs to treat schizophrenia patients is drugs, antipsychotics, that have a lot of baggage. They're very suboptimal drugs. They have a high side effect burden. they're used in those populations because the medical need is so significant. And so, and we don't have better alternatives yet. And that's one of the reasons that those drugs are not approved for use in Alzheimer's disease psychosis patients or Parkinson's disease psychosis, for that matter, any dementia-related psychosis. When you get to these more frail and elderly patients, you need to have, obviously, a drug that works. You need to have a strong antipsychotic effect. But it is equally important to have a drug that is very, very safe and extremely well tolerated. Because the bar for tolerability issues is just a lot higher. And so, I think, you know, we have a, I'm very excited about some of the very exciting work going on in the muscarinic area. I'm hopeful that it'll lead to improved antipsychotics. And I think the area where there's the greatest opportunity is in schizophrenia. We'll have to see how the profile of those kinds of drugs emerges and evolves to assess how well positioned they'll be in the more elderly and frail populations. One thing we know about Pimivanserin and the profile and the area that we're working in with 204 by implication is that this mechanism that we're working through in serotonin is very well tolerated. It's a very different profile than what we typically see with antipsychotic drugs today. So, again, I think the key element there will be not only efficacy, but also safety and tolerability. And I'll ask Serge if he has anything else he'd like to contribute.
spk10: Yeah, I second everything Steve said. I would just add one other element, and that is we have on our side quite a bit of experience with this mechanism and this patient population. And we intend to use that experience and knowledge to our competitive advantage as we are designing the trials and moving through development of ACV204. Okay, great. Thank you.
spk14: Thank you. One moment for our next question. Our next question comes from the line of Jeff Hung from Morgan Stanley.
spk03: Thanks for taking my question, and Serge, my congratulations, too, on your upcoming retirement. Can you just talk about what drove the reduction of the in-channel inventory, and is this something that might happen again in 4Q, or should we expect inventory to go back to prior levels? Appreciate any call you can provide. Thanks.
spk09: Yeah, thanks so much for the question, Jeff.
spk03: Mark, do you want to take that?
spk08: Sure. Thanks for the question. Now, as we speak to our channel partners, I think there are a number of factors influencing the overall reduction in inventory levels. First, their inventory needs to become more predictable as new plazid volumes remain in this stable to moderate growth period. Their cost of capital has also increased due to recent increases in interest rates and continued inflationary pressures. And third, kind of with the IRA, you know, future price increases may become more predictable for our partners for Medicare-related drugs, and this can influence the timing of their inventory purchases, purchase decisions. And, you know, going forward, you know, inventory always fluctuates from quarter to quarter, and over the long term, we expect, you know, our sell-in to match, you know, demand with respect to in-channel inventory purchases.
spk09: Thanks.
spk14: Thank you. One moment for our next question. Our next question comes in the line of Mark Goodman from SVB Larynx.
spk02: Yes, hi. With respect to SG&A, can you just give us a sense of what is going on? It appeared that you were taking down some spending, and then it's going to pop back again this next quarter, given your guidance. So just give us a sense of what you're doing out there with New Plaza's And are you doing any more DTC? Are there plans for that? How should we think about SG&A into next year? Just give us a sense of the ebbs and flows because it looks very strange. Thanks.
spk06: Mark, do you want to take that?
spk08: Sure, no problem. Thanks for the question. I think as we look over the course of the year, we have reduced our SG&A spend principally by reduction in selling and marketing expense. We've not run a DTC campaign this year. We'll look to that in the future as we potentially see that being a positive ROI investment, but to date, we haven't done that, and we'll keep you informed if we change our mind as we move forward. Quarter to quarter, it does fluctuate. There's some seasonality to some of our expenses, so that's what you're seeing, we continue to just be in line for our year expectation for total SG&A spend, which is why we just reduced the range of our guidance and kept it at the midpoint. And from when we go next year, clearly we'll give Now, guidance when we do our fourth quarter earnings call for next year, what we mentioned kind of during the second quarter call, it just holds true today that we expect our overall and just SGA spend to be approximately the same next year as it is this year as we will use, you know, as we'll certainly have a budget to ensure a successful launch for Trifinitide while also just continuing to, you know, optimize and be efficient with our spend on PDP.
spk02: Will R&D also be flattish for next year, or do you think that'll be a step up?
spk08: So I think, you know, again, I just share what we did last quarter. And R&D is a little bit different just because of, you know, the impact of business development payments. So if you take that out, which can fluctuate from year to year, and as a reminder, kind of within kind of year-to-date expenses for R&D were about, you know, about almost at $80 million of PD payments, the largest of which is this built-up front payment of $60 million. So taking that aside, we do have an expectation just with kind of the ongoing kind of new and continuing programs that are spent based upon the portfolio that we have today will reduce approximately $35 million in R&D spend next year. Thanks.
spk14: Thank you. One moment for our next question. Our next question comes from the line of Paul Matias from Stiefel.
spk22: Hi, this is James on for Paul. Maybe just a quick one on ACP 204. I guess given your experience with Pimavanturin and kind of, you know, anything you've learned in your interactions with the FDA as it relates to ADP, I guess, how are you thinking about clinical development going forward? Of course, you're in phase one now, but I guess as you think about future trials, have you kind of thought about or gotten any sort of, I guess, guidance on a kind of design and path forward that would be most productive for, I guess, kind of a rapid development path in ADP? Any color there would be great. Thanks.
spk06: Yeah, thanks much. Let me, I'll open the aperture up a little bit and then try to focus down on your precise question. With ACP204, I think we'll have multiple indications that we will want to consider in development once we exit phase one. The top of the list, just to be absolutely clear, as you alluded to, is ADP. We know today that Pimivanserin will only be approved in Parkinson's disease psychosis and possibly negative symptoms of schizophrenia, and then possibly autism, where we're running pediatric studies now. That leaves a lot of indications where new plans will not be approved. And that's one consideration, not the only, but certainly one consideration in terms of where we want to go with 204. So as it relates to ADP, we know a lot about this mechanism. We know a lot about the chemical space we're operating in. That gives us a reduced risk profile as we move forward. And that gives us the potential for moving more aggressively through this space. We also know a lot about ADP. We have a really good feel for how patients respond to antipsychotic treatment, et cetera. So I think all those things together put us in a position where we, as I mentioned, have prioritized ADP as our first indication to pursue. and put us in a position where we think we can likely move very aggressively in that indication. Serge, anything else you want to add?
spk10: Just a little bit of additional color of our experience in conducting trials in this patient population and working with the sites worldwide also provide us with valuable experience and lessons in terms of selecting the right patients and selecting the right sites for these trials, not only from a perspective of the speed of recruitment, but also quality of patients and quality of data that we can generate.
spk09: Thanks so much.
spk14: Thank you. One moment for our next question. Our next question comes from the line of Jay Olson from Oppenheimer.
spk21: Oh, hey, thanks for taking the question. And I want to add my congrats to Serge and all the best to you for your retirement. Based on the preclinical profile of ACP204, can you talk about your expectations for the potential clinical advantages of 204 that could be demonstrated when compared to Pima-Vansarin and how you plan to leverage those advantages? Thank you.
spk06: Yeah, sure. Serge, you want to go ahead?
spk10: Yes. Thanks, Jay. Thanks for the good wishes. What I would say is that the principal advantage that we are seeing with HCP204 is in a favorable tolerability profile that so far we have been seeing through the clinical development. And that's important on several levels. One, QT liability and potential to eliminate the mild signal that we have with Pimavancerine provides us with the opportunity to expand the dose range that we can evaluate, and by that, potential to actually evaluate a better efficacy and identify the more efficacious doses, which we had certain limitations with Pima-Vanserin. In addition, overall, as I said, overall tolerability provides us with a good opportunity to evaluate efficacy in the context what Steve earlier mentioned, and that is the safety, which is very important for this patient population.
spk21: Excellent. Super helpful. Thank you very much.
spk14: Thank you. One moment for our next question. Our next question comes from the line of Salveen Richter from Goldman Sachs.
spk01: Good afternoon. Thank you for taking my question. Just wanted to get a sense of how you're thinking about the trajectory for PDP in 2023 and beyond, just given the channel dynamics that you've noted.
spk06: Thanks so much for the question, Salveen. Brendan, you want to take that?
spk07: Sure. Thanks, Salveen. There's the current environment in which we operate and then the future environment that we envision. So for me, I think we're seeing the early indicators of improvement in long-term care. If those continue, I like the trajectory we're seeing for New Placid, both in terms of market itself and our individual performance. As I said in my prepared remarks, our quarter-over-quarter growth is outpaced Carbidopa, Levodopa, and the top 15 LTC brands. That gives me confidence. both that we have a favorable market environment, but also that we have the right message that we're delivering to clinicians there. Similarly, in the inpatient community setting, I think what we see is stability. And my hope is, pending continuing improvement in the environment around us, that PDP patients will begin returning to the in-office setting. Regardless of that, you see the way we're approaching the business on the community side, which is leveraging real-world evidence to go after share in the first-line setting. So for us, I think you should expect to see a posture of putting material in front of these physicians that have the deepest pools of patients and demonstrating the real-world outcome differences that should suggest a higher use of New Plaza in the first line setting. So for us, I think in the community, you'll see us more and more competing for share in the community.
spk06: Brendan, you want to just remind everyone what the real-world evidence publications are that you're referring to and kind of the timing of those? Sure.
spk07: Thanks. Thanks for the question. The important differences that are being brought to light, these are, I would call this an emerging body of evidence that supports the use of New Plaza versus off-label multi-receptor antipsychotics. We've had our first opportunity in the middle of the third quarter to share information that is looking at all-cause hospitalizations, ER visits, psych visits, and nursing home stays. all of which are demonstrating significant advantages for New Plaza versus all other atypical antipsychotics. That's attractive on two levels. It's attractive clinically because obviously you're looking to make the best decision for residents in a long-term care facility. It's also attractive from the economics of avoiding rehospitalizations for which facilities are looking for appropriate reimbursement. I think that that information is resonating. Again, we're very early on in the discussions of that data. Didn't really start until the middle of the third quarter. The second data set, also very compelling, we started sharing early in the fourth quarter, and that's a recent publication in the American Journal of Psychiatry. It's important because neurologists don't generally get the American Journal of Psychiatry, so it's not data that they would necessarily have seen on their own. It's a retrospective Medicare claims analysis that compares the risk of all-cause mortality associated with Nuclasid versus all other atypical antipsychotics used off-label in patients with Parkinson's disease psychosis. And importantly, there is a large subset that are receiving low-dose quetiapine, which is principally the therapy that might otherwise be used instead of Nuclasid. The authors concluded that pimavantrin was associated with an approximately 23% lower mortality than the other atypical antipsychotics over 360 days. For us, that is very compelling information, very informative to HCPs as they make decisions about how to treat their patients and residents. Again, we're very early on in the dissemination of that data, but we are encouraged by the community's response to it.
spk14: Thank you. One moment for your next question. Our next question comes from the line of Yateen Suneha from Guggenheim Partners.
spk12: Thank you for taking my question. I have a couple on RET given that I think it's going to be a focus next year. So can you maybe frame for us how should we think about a ramp or a launch there? We understand, you know, there are about 4,000 or 4,500 patients diagnosed. How many you might have a line of sight on? How should we think about the label? and the pricing? I understand early, but maybe give us some calm to think about things.
spk06: Yeah, I'm sure. I'll start, and then I'll ask Brendan to touch on it as well. So, I think as we think about kind of the shape of the curve on launch and Rett syndrome, our anticipation is it will be a linear type of progression. Sometimes in rare disease, you have Expanded access programs. We have a large bolus of patients that suddenly convert to commercial pay patients. We, I think, for very good reasons, we did not do that here. And so, so, as we get the drug approved and launched, it does take a little bit of time to get on formularies. It does take a little bit of time to work through the access process. Of course, a lot of the early scripts will be based upon letters of medical necessity, but it does take a little bit of time to get everything in place so that you begin ramping up. So, for all of those reasons, we anticipate a very attractive, a linear-shaped curve in the early days and quarters of the launch. As we move beyond that, we do have a fairly sizable prevalent population and then an incident population beyond that that will continue to provide attractive growth opportunities as we go forward. Brandon, I'll turn it over to you and let you address the other part of the question.
spk07: Sure. Thanks, Steve, and thank you for the question. As I said in my prepared remarks, and I think what's been very encouraging to us is we've been able already to map that HCP target universe and the database, as Kathy also alluded to, of patients that we know are already being treated and where they're being treated. So we have that as an advantage to know where to be at the time of launch at these IRS centers of excellence. Another big a number of patients that are treated at non-COE academic institutions, and we know some of the targeted neurology practices where these patients will be treated. To Steve's point, the feedback from payers has been that they treat rare diseases largely similarly, and their feedback to us does suggest that they will go through their normal processes with trofinetide. So I think Steve is absolutely right when it comes to sort of a normal early trajectory you'd expect in a drug like that in a rare disease setting. As you mentioned, I would say it's premature for us to discuss price, but I think you know how Acadia has viewed price in the past. We match price with the value we think the product is imparting, and we absolutely want to make sure we ensure access to the trofenetide community. I would view trofinetide as having unequivocal efficacy and a tolerability profile that is very well received. We know we're treating the core symptoms of a devastating disease, and we know that we're looking to make meaningful difference in the lives of patients and their families. And as a function of that, I would expect that we'll price the product in the range of other rare pediatric disease products to give you just some sense of direction.
spk14: Thank you. One moment for our next question. Our next question comes from the line of Danielle Brill from Raymond James.
spk04: Hey, guys. This is Alex for Danielle. Forgive me for asking the same question basically two quarters in a row, but I know you mentioned you presented lavender and daffodil at some medical conferences. Did those presentations include the open-label LILAC studies? And if not, when do you expect to present those data?
spk09: Jason, you want to take that?
spk19: Yes. So, for the first open-label study, LILAC 1, we'll be completing that study near the end of this year. As I mentioned, we submitted an interim data cut. as part of the NDA, but the study completion is at the end of this year. And then we anticipate submitting that for presentation at medical offices most likely in the spring.
spk20: Great, thanks.
spk14: Thank you. Our next question, one moment for our next question. Our next question comes in line with Sumant Kulkarni from Canaccord Genuity.
spk15: Good afternoon. Thanks for taking my question, and I'll add my best wishes to Serge on his upcoming retirement. So on the Parkinson's disease market, do you think Acadia is optimally resourced to capitalize on a potential return to normal? Or is the issue outside of the company's control and has the pandemic simply amplified a larger issue related to a positive innovation or excitement in terms of other novel products for Parkinson's that's driving fewer office visits, for example?
spk07: Yeah, brilliant. Do you want to take that? Yeah, sure. Thanks for the question. I think what we've seen is and has somewhat continued to be temporal. But the early indications that we're seeing in the long-term care channel have been favorable. And they are demonstrating a differential preference for New Placid over a competitive set. So, for me, I find that very encouraging. When I look at the real-world evidence that is now available to us, it really hasn't existed for the treating community to have previously. Pimavantrin was approved versus a placebo in a placebo-controlled study. There are clinicians out there that think that it is every bit as logical to use some of these off-label atypical antipsychotics because they really haven't seen any contrast between those two therapies. Now, I think we have a growing body of evidence that states that there really is a meaningful real-world difference and I am enthusiastic about our opportunities moving forward in the quarters ahead. Again, it's early on, but with our market share at or around 20%, there's plenty of room for us to continue to grow the brand, and I think a nice scientific platform that provides that differentiation for us. Thanks.
spk14: Thank you. One moment for our next question. Our next question comes from the line of Gregory Renza from RBC.
spk20: Hey, Steve and team. Thanks for taking my question and also let me add my well wishes to search as well. Just a quick one on business development, Steve. I was wondering if you could update us on any of the latest catalyzing or even gating factors to accelerating those external investments and efforts. And just curious if at all IRA and inflation reduction has an input to you on how you're thinking about the evolving pipeline and looking externally. Thank you very much. Yeah, yeah.
spk06: Thanks so much for the question, Gary. Look, as we indicated earlier, you know, we've been successful in business development. Trepenta has a great example of that. But we've had an enormous competitor for the last five to seven years, we and everyone else, and that is the capital markets. And I think as the capital markets have turned to be less supportive and stable, you know, that does, that will have a read-through on business development. We've seen this in prior cycles like this. But it usually takes a while. It usually takes, you know, three or four quarters for it to kind of realize the whole impact of that. So, you know, we don't, as we indicated, we don't need to raise capital. So we, in some respects, the capital market's becoming less of a competitor and business development is really, net-net is just a positive for us. And so I think we are beginning to see across the business development landscape a change. Some companies just having a harder time financing their business, particularly those who don't have a strong balance sheet and don't have revenues and cash flow and need to finance their business from Wall Street. And so as a consequence, I think if the capital markets stay choppy for the foreseeable future, then I think that the pressure on these companies to get more aggressive on business development, which is grow and grow. And I think we're very well positioned to be beneficial at that. So as we look forward to our footprints in both psychiatry, neurology, rare disease, and broad applications, we think there's a growingly attractive opportunity, a more and more attractive opportunity to leverage those capabilities through BD.
spk20: Got it. Thanks, Steve. I appreciate the caller.
spk09: And Greg, was there a part two to your question? I'm sorry, I think there was.
spk06: I think there was a part two to your question, Greg. I'm trying to recall what it was.
spk08: It's whether the Inflation Reduction Act will impact our decision for development.
spk06: Thanks. Yeah, Greg may prop up. Look, I think the answer is it's going to have a pretty significant impact on our industry, I think, over time. And so, you know, from a I think we begin to see some evidence of that just in the last week or so, right? And so I think over time, people will be much more conscious of modality, small molecules versus large molecules, and they'll be more sensitive to payer mix. And so I think it will have an impact on our industry, and therefore it will also have an impact on business development assessments.
spk14: Thank you. I am sorry that we are out of time. Mr. Davis, please proceed to closing remarks.
spk06: Great. Thanks much, operator. Well, thanks much for all of you for listening in. We look forward to updating you next quarter.
spk14: Thank you for your participation in today's conference call. This concludes the presentation. You may now disconnect. Good day.
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